Urea-containing chewable antacid tablets



United States Patent 3,452,138 UREA-CDNTAINING CHEWABLE ANTACID TABLETSEdmund S. Granatek and Alphonse P. Granatek, Baldtablets is such thatthey are too gritty as a practical matter to be conveniently chewed toany finer particle size.

The antacid activity of a given tablet can therefore Winsville, N.Y.,assignors to Bristol-M Company 5 be measured, when particle size istaken into account, New York, N.Y., a corporation of Delaware by thePmcedure of Fuchs, g d m ti In- No Drawing Filed Aug 26, 19 4 Sen 392259 dustry, 64, 692 (1949). As this method was used herein I t, C],A611; 27/06 a reaction vessel was charged with 25 ml. of 0.1 N US. Cl.424-455 4 Claims hydrochloric acid and 125 ml. of deionized water. TheThis invention relates to particularly elegant and effec- 1O reactlonVessel eqlllpped WItDh gm l' and pH tive antacid tablets and, moreparticularly, to a chewable electrodes and mamtalned at 37 C. :1 maconstant antacid tablet comprising a major proportion of Watertemperature bath. Intact tablets were placed in a U.S.P. insolubleantacid agent, a major proportion of mannitol dlsintegration apparatusand introduced directly into this and a minor proportion of urea"reaction medium. The powdered tablets were first wet Aqueous suspensionsof antacids such as aluminum f P F 10% Solutlon of a Wetfmg agenthydroxide, alone or in combination with other antacids five of Water anddiluted with such as magnesium hydroxide, are effective medication anaddltlogal 1111- Of Water- T 2? ml. of 0.l N for the control of gastrichyperacidity and gastric ulcers. y q l p 9 was then added mm diately andagita- In the practical management f these conditions however t1oninitiated simultaneously. The surfactant was found the need exists for adosage form which is more con- 20 necessary to assure wettlng 511166 they phobic nature venient and readily available to the patient during histhe Fonlponents In y of the tablets P v n ed ready routine, dailyactivities. Tablets have been used to meet dlspefslonthis need but formaximum usefulness such tablets must Wlth h Start of lmmerslon oragltatlon, the PH was be capable of being chewed and swallowed withoutwater recorded lmmedlatflly and at e d f the first, thlrd, and ifchewed, be free of objectionable characteristics fifth P tenth lllmutes-All thls P and after ach and must also provide sufiicient antacidactivity. ten m readlng thereafter, 1 ml. Of 1.0 N hydro- It is commonlyaccepted that the human stomach conchlor 9 Was added- The Procedure as fllOWed until tains about ml. of 0.1 N hydrochloric acid after a thellsadlng Was below P 3 l the l X increment meal. During the next twohours this will be supplemented of acld was due to be added- Trlpllcateruns Were made, by the secretion of about 240 ml. of 0.1 N hydrochloric30 and the results averaged acid. It is expected that patients secretinglarger amounts A Fablet W t not consldered 9 p f isfactory ofhydrochloric acid will be able to obtain relief by taking q actlvltyunless the p i t is test was held a suflicient number of doses of anantacid as measured wlthln the range of P for all least elghty by theirown observed relief from discomfort. It is also r mlnutesrecognized thatan individual with a gastric ulcer will Ten antacid tablets of thecomposition listed below in TABLE Ave. Comb. active ingredients perAverage tablet Composition Labeled dosage and instructions tabletweight, grams Calcium carbonate, glycine 1 orh2 tablets as needed, chew,melt in mouth o s ll 600 651 \V O G. Dried aluminum hydroxide gel(stabilized With hexitol), 2 to 4 tablets as necessary, chewed orswallowed whole. 395 690 magneisum hydroxide. Aluminum hydroxide,magnesium hydroxide 2 to 4 tablets, chewed or swallowed 4 4 Aluminumhydroxide with magnesium hydroxide 1 or 2 tablets as required. May bechewed before swallowing 420 925 Dried aluminum hydroxide gel Swallow 1or 2 tablets 324 2 Dried aluminum hydroxide gel, magnesium trisilicate,1 or 2 tablets chewed, sucked or taken with water as .520 .987

magnesium hydroxide. necessary. Aluminum hydroxide-magnesium carbonateco-dried gel 1 or 2 tablets as required. Chewed or swallowed .375 1. 634

in a dextrose and milk soilds base. Aluminum hydroxide, magnesiumhydroxide 1 1 0r 2 tablets, may be chewed or swall w d with at 420 923Dried aluminum hydroxide gel 1 1 or two tablets 324 993 Magnesiumtrisilicate, dried aluminum hydroxide gel 1 to 4 tablets as necessary, cewed, swallowed or allowed to 748 1. 340

disintegrate in the mouth.

1 Australian products.

obtain relief by adjusting the contents of his stomach to a pH of from 3to 5. Any lesser pH will result in pain from the acid and any pHsubstantially greater than 5 will result in the highly undesirablephenomenon known as acid rebound as is observed, for example, whensimple sodium bicarbonate is used as an antacid.

It is further recognized that any test of the antacid activity of thetablet must take into account the manner in which it disintegrates inthe stomach and the size of the particles into which the tablet has beenbroken if it is chewed before it is swallowed. The USP. XVI tabletdisintegration test has been used extensively to simulate the conditionswhich prevail in the human stomach. Examination of commerciallyavailable antacid tablets after they have been chewed and expectoratedshows that the majority of particles are no finer than sufiicient topass a IO-mesh screen; the nature of the material in these the tablewere obtained from the open market in the USA. or Australia and theirduration of action in the effective range of pH 3.0-5.0 in minutes wasmeasured.

To provide the proper analogy to conditions in the human body it wasalso necessary to take into account the particle size afterdisintegration of these tablets. This was done in two ways.

In the first method the tablet in the acid reaction cell was placed in abasket having a IO-mesh screen on the bottom which was raised andlowered as in the U.S.P. disintegration test. This simulated theconditions found when the tablet was swallowed without chewing.

In a second test the tablet was ground to pass a lO-mesh screen(simulating the size obtained when the tablet was chewed and thenswallowed), placed in the acid of the reaction cell and mixed with aperforated disc which was raised and lowered as in the U.S.P.disintegration test.

It was found that, under these conditions simulating what actuallyoccurs in the human body, such commercial tablets in general failed toprovide anything approaching their theoretical buffering capacity. Forexample six of the ten whole tablets never raised the pH to the minimumsatisfactory level of pH 3 and one of the ten whole tablets quicklyraised the pH above the maximum acceptable level of pH 5 and kept itthere for a considerable time.

When the tablets were ground to -mesh to duplicate the effect of chewingprior to swallowing, only one gave a duration of action greater than 65minutes in the desired range of pH 3-5 and six of the tablets remainedin the effective range for periods of less than 40 minutes with two ofthem not reaching that range at all and another going above pH 5 for allbut 16 minutes. In addition, the three tablets which when 10-meshremained in the effective range of pH for 65, 65 and 90 minutesrespectively, were each evaluated as being much too grittty uponchewing. This would obviously militate against their continued use andchewing by the patient for the extended periods of time over which thesetablets must be taken by patients with gastric ulcers. It was thereforeapparent that the presently available antacid tablets as judged by theten different products tested were far from being acceptable antacidagents.

Chewable tablets of other types of pharmaceutical agents, e.g.antibiotics, have been formulated using large amounts of mannitol in thetablet but this is not practical in the case of antacids such asaluminum hydroxide and the like because such tablets if of a reasonablysmall size are much too astringent and dry to chew without water, i.e.antacid agents of this type dry up the mouth to an unacceptable extent.

The use in ordinary antacid tablet formulation of agents such asaluminum hydroxide in finely divided form (e.g., greater than ZOO-mesh)is customary but fails to provide particles of such small size in thestomach when used. This undesirable effect may be due to the compressionwhich must be applied to form the tablet or due to the otherconventional manufacturing procedures used in preparing the tablets.Other common expedients do not serve to provide the proper particlesize. Thus, use of wetting agents gives too bitter a taste. Admixturewith simple water-soluble substances is not effective; thus, sodiumchloride is too saline, sucrose is too sweet and lactose is noteffective.

It was therefore the objective of the present invention to provide anantacid tablet, e.g., of the type containing aluminum hydroxide alone orin combination with similar antacids such as magnesium hydroxide, whichwould provide, as measured by the test described above, a duration ofaction in the effective range of pH 3-5 of at least 80 minutes and whichwould also have chewing properties of sufficient elegance to encourageand make possible longterm use, i.e., would give a feel in the mouthupon chewing which was not astringent, pasty, dry, chalky or slimy,which was neither too hard nor too soft when chewed and which was notgritty when chewed and which could be chewed and swallowed withoutwater.

The objects of the present invention have been achieved by theprovision, according to the present invention of a chewable antacidtablet comprising a major proportion of water-insoluble antacid agent, amajor proportion of mannitol and a minor proportion of urea.

Preferred embodiments of the present invention are a chewable antacidtablet comprising by Weight 35 to 60% of water-insoluble antacid agentselected from the group consisting of aluminum hydroxide, magnesiumhydroxide, magnesium oxide, magnesium carbonate and magnesiumtrisilicate and mixtures thereof, at least about 25% and preferablyabout 25 to 50% of mannitol and about 4 to 10% urea; a chewable antacidtablet comprising by weight about 35 to 60% of water-insoluble antacidagent, said agent being a mixture consisting of more than one-half 4aluminum hydroxide and less than one-half magnesium hydroxide, about 25to 50% of mannitol and about 4 to 10% urea; a chewable antacid tabletcomprising by weight about 50% of water-insoluble antacid agent, about35% by weight of mannitol and about 7% by weight of urea.

The water-insoluble antacids used in the tablet of the present inventioninclude the hydroxides, carbonates, trisilicates and oxides of aluminum,magnesium and calcium and other known neutralizing agents such as aredisclosed above and in textbooks of pharmacy and medicine and, forexample, in U.S. Patents 1,964,696; 2,446,981; 2,588,- 090; 2,641,604;2,686,800; 2,797,978; 2,802,773; 2,907,- 781; 3,047,602 and 3,099,524and mixtures thereof.

The term antacid agent as used herein includes both such individualcompounds and mixtures thereof.

The tablets of the present invention contain, when desired, sweeteningagents, flavors, tableting lubricants, fillers and the like and may alsocontain additional therapeutic agents such as antispasrnodics (e.g.,aminopentamide), antisecretory agents, tranquilizers (e.g., reserpine,meprobamate), antiflatulents (e.g., methylpolysiloxane), sedatives(e.g., phenobarbital), analgesics, local anesthetics or compatiblecombinations thereof.

Included within the present invention is the process of preparing achewable antacid tablet which comprises first blending a majorproportion of antacid agent and a major proportion of mannitol with aminor proportion of urea, next further reducing said mixture in particlesize by mechanical means and 'finally forming said mixture into tablets.

The following example will serve to illustrate the present invention butthe invention is not limited thereto and includes within its scope suchvariations in ingredients and proportions thereof as are well known tothose skilled in this art.

EXAMPLE Formula Per tablet, gm. Aluminum hydroxide, U.S.P., dried gel,medium powder 0.300 Magnesium hydroxide, NP. 0.090 Mannitol, N.F.,ZOO-mesh 0.300 Urea, N.F., 60-mesh 0.060 Sodium Sucaryl, ZOO-mesh 0.020Sodium saccharin, U.S.P. 200-mesh 0.002 Corn starch, U.S.P. 0.0133Flavors 0.013 Magnesium stearate, U.S.P. 0.0456

Tablet weight, anhydrous basis 1 0.8439

Finished tablet weight must be adjusted to include the Water remainingin the granulation after drying.

MANUFACTURING INSTRUCTIONS FOR 1,000 TABLETS (1) Prepare 266.0 grams of5% (w./w.) starch paste by heating 13.30 grams of corn starch dispersedin 252.7 ml. of purified water, U.S.P., to boiling. Sufficient agitationshould be used during this step to avoid scorching. Remove heat andmaintain agitation until cooled to 25 C. Add sufiicient purified water,U.S.P., to bring the weight up to 266.0 grams and mix to obtain ahomogeneous paste.

(2) Combine the aluminum hydroxide, magnesium hydroxide, mannitol, urea,sodium Sucaryl and sodium saccharin (e.g., in a pony pan) and blend atslow speed for 15 minutes.

(3) Pass the blend through a milling machine to break up any lumps (e.g.through a Fitz mill at high speed with impact forward using a M00screen).

(4) Return the milled material to blender and continue mixing forone-half hour.

(5) With agitation in the blendor remaining at low speed, rapidly addall of the starch paste from step No. 1 and mix until a uniformdispersion is obtained. The mix appears dry at this point but usuallycontains enough moisture to form the granulation. If necessary,additional water may be added to facilitate the formation of the strandsof granulation described in the next step.

(6) Pass the mix through a granulator (e.g., a Stokes oscillator, withfunnel removed using a No. 6 mesh stainless steel screen) and collectdirectly on drying trays. If strands of granulation are not beingformed, additional water must be added to the mix.

(7) Spread the granulation evenly on the trays and dry (e.g., in aStokes oven) at 38 C. until the moisture content is 45-55%.

(8) Mill using a combination of screen, speed and blade adjustment whichwill produce the greatest yield of 30- to 60-mesh granules.

(9) Separate the granules retained on a 60-rnesh screen, add 5.48%magnesium stearate and hold.

(10) To the fines passing through a 60-mesh screen add 5.48% magnesiumstearate and blend thoroughly.

(11) Slug at a weight of 0.470 gram using /2 inch, flat punches to ahardness of 5 to 7 kg. Reduce the slugs to 30- to 60-mesh granules andrepeat the process until not more than nor less than 10% of finespassing through a 60-mesl1 screen remain.

(l2) Combine the lubricated granules from step No. 9 with the granulesand fines from step No. 11. Add the flavors and blend thoroughly for 30minutes.

(13) Tablet using /3 inch, flat, beveled edge punches to a hardness of11 kg. or /2 inch square, concave punches to a hardness of 9 to 10 kg.(Strong-Cobb-Arner tester).

These tablets when chewed and expectorated were found to pass a 100-meshscreen. These tablets when ground to l00-mesh and tested as describedabove gave a duration of action in the effective pH range (3.05.0) of 81minutes. The chewing properties of these tablets were evaluated asfollows:

Flavor Very good. Mouth feel Cooling. Chewing characteritsics Very good.Chewing hardness Medium. Not gritty.

While in the foregoing specification various embodiments of thisinvention have been set forth and specific details thereof elaboratedfor the purpose of illustration, it will be apparent to those skilled inthe art that this invention is susceptible to other embodiments and thatmany of these details can be varied widely without departing from thebasic concept and spirit of the invention.

We claim:

1. A chewable antacid tablet comprising by weight about 35-60% ofwater-insoluble antacid agent selected from the group consisting ofaluminum hydroxide, magnesium hydroxide, magnesium oxide, magnesiumcarbonate and magnesium trisilicate and mixtures thereof, about 25-50%of mannitol and about 410% urea.

2. A chewable antacid tablet comprising by weight about one-halfwater-insoluble antacid agent selected from the group consisting ofaluminum hydroxide, magnesium hydroxide, magnesium oxide, magnesiumcarbonate and magnesium trisilicate and mixtures thereof, about onethirdmannitol and about one-tenth urea.

3. A chewable antacid tablet comprising by weight about 35 to 60% ofwater-insoluble antacid agent, said agent being a mixture consisting ofmore than one-half aluminum hydroxide and less than one-half magnesiumhydroxide, about 25 to of mannitol and about 4 to 10% urea.

4. A chewable antacid tablet comprising by weight about one-halfwater-insoluble antacid agent, said agent being a mixture consisting ofmore than one-half aluminum hydroxide and less than one-half magnesiumhydroxide, about one-third mannitol and about one-tenth urea.

References Cited UNITED STATES PATENTS 6/1958 Goodfriend l6755 12/1965Ainsworth 167-55 OTHER REFERENCES ALBERT T. MEYERS, Primary Examiner.

S. FRIEDMAN, Assistant Examiner.

US. Cl. X.R.

1. A CHEWABLE ANTACID TABLET COMPRISING BY WEIGHT ABOUT 35-60% OFWATER-INSOLUBLE ANTACID AGENT SELECTED FROM THE GROUP CONSISTING OFALUMINUM HYDROXIDE, MAGNESIUM HYDROXIDE, MAGNESIUM OXIDE, MAGNESIUMCARBONATE AND MAGNESIUM TRISILICATE AND MIXTURES THEREOF, ABOUT 25-50%OF MANNITOL AND ABOUT 4-10% UREA.